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PHARM 141 > Trials and Drug Development > Flashcards

Trials and Drug Development Flashcards

1
Q

Why conduct pre-clinical studies?

A

Government regulatory requirement to show quality, safety and efficacy of new drugs

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2
Q

What is the elixir of sulfanilamide disaster of 1937?

A

Not tested for safety and caused over 100 deaths, many of them children –> animal testing could have predicted this toxicity

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3
Q

When was Health Canada formed and what do they do?

A

1993 –> oversees all areas of healthcare including regulation of food, drugs, environmental and pesticide safety, etc

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4
Q

What is the drug regulatory agency in Canada?

A

TPD = Therapeutic products directorate

The body that reviews and approves drugs that a sponsor wants to market.

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5
Q

What is HPFB and what do they do?

A

HPFB = Health Products and Food Branch

Mandated to take a integrated approach to the management of the risks and benefits to health related to health products and food by:

  • minimizing health risk factors
  • maximizing safety
  • promoting conditions that enable Canadians to make healthy choices
  • providing information so Canadians can make informed decisions about their health
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6
Q

What are preclinical studies?

A

Studies conducted in the development of a medicine, other than those in humans including in vitro studies and animal studies

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7
Q

What should pre-clinical studies assess?

A

What does the body do to the drug? (ADME)
What does the drug do to the body? (efficacy and safety)
What are the benefits and associated risks and costs?

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8
Q

What are the stages of molecular attrition in drug development?

A
  • 5000-10,000 molecules screened for activity in vitro
  • 250 enter non-clinical testing (essentially animal testing)
  • 5 enter clinical testing in humans
  • 1 gets approved by the FDA
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9
Q

What are the goals of pre-clinical trials?

A
  1. identify major organs and organ systems that may be targets
  2. characterize dose and time relationships of adverse effects
  3. seek markers of activity, effect, and toxicity
  4. gather more evidence for the initial phase 1 rials in humans
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10
Q

What are the 14 types of studies needed to conduct in order to support the administration of the drug to humans?

A
  1. Pharmacology studies
  2. Pharmacokinetic and pharmacodynamic studies
  3. Acute toxicity studies
  4. Repeated-dose toxicity studies
  5. Estimation of first human dose
  6. Local tolerance studies
  7. Genotoxicity
  8. Carcinogenicity studies
  9. Reproduction toxicity studies
  10. Immunotoxicity
  11. Photosafety
  12. Non-clinical abuse liability
  13. Other: skin irritancy, pediatrics, worker safety, environmental impact
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11
Q

T or F: repeat dose toxicity studies required to support clinical trials in humans are done only in rodents.

A

False, they are done in both rodents and non-rodents for MINIMUM the amount of time that a human would take it

(with the exception of single dose, where toxicity studies are 2 weeks minimum)

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12
Q

What are the key pieces of information that is gathered from safety and toxicity studies in animals?

A
  • identification of target organs and nature of toxicity
  • information about the mechanism
  • dose-response profile
  • time-response profile
  • special safety monitoring needs in clinical trials
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13
Q

How do you select a dose for clinical trials?

A

NOAEL calculated for the most appropriate animal species and converted to human equivalent dose based on weight or BSA

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14
Q

What is the meaning of caveat?

A

There is no absolute assurance that the safety or efficacy observed in animals will fully reflect that in humans

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15
Q

What is the difficulty with in vitro toxicology studies?

A

Demonstrating effects involving multiple organs or tissues since the thing being studied are isolated organs, cells, cell fractions or isolated proteins

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16
Q

What is an advantage of in vitro toxicology studies?

A

often excellent tools for screening or investigating mechanisms

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17
Q

What is ‘in silico’ toxicology?

A

Relies on ‘structure predicts biological activity’ or on class observations (rule-based)

May exclude a high proportion of potentially viable molecules (false positives), but suited to high throughput screening

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18
Q

What is the timeline and cost for pre-clinical studies?

A

1.5-6.5 years and 4-6 million dollars

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19
Q

What is an IND?

A

IND = investigational new drug (US)

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20
Q

What is a CTA?

A

CTA = Clinical trial application (Canada)

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21
Q

When is the review completed after submitting a CTA?

A

within 30 days

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22
Q

What is the IRB?

A

IRB = Institutional Review Board

Oversees clinical trials

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23
Q

What are the two responsibilities of the industry when conducting clinical trials?

A

1) Subjects are to be exposed to the least possible risk

2) Empiricism

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24
Q

How is exposing subjects to the least risk accomplished?

A
  • permissive/supportive animal testing
  • qualified and experienced investigators
  • oversight by IRB
  • informed consent
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25
Q

How is empiricism accomplished in clinical trials?

A
  • deliberate sequence of controlled events
  • timely and sequential reliance on animal data for potential irreversible, not readily apparent toxicity
  • post-marketing surveillance, registries and epidemiology
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26
Q

What are the benefits for participating in clinical trials?

A
  • play an active roll in their own healthcare
  • gain access to new research treatments before they are widely available
  • obtain expert medical care at leading HC facilities
  • help others by contributing to medical research
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27
Q

What are the risks of participating in clinical trials?

A
  • may be unpleasant, serious or life-threatening side effects to experimental treatment
  • experimental treatment may not be effective
  • protocol may require more time (trips to the site, more treatments, hospital stays, or complex dosage requirements)
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28
Q

What are the stages of clinical trials AFTER the submission and review of the CTA?

A

Phase 1: pharmacological studies
Phase 2: preliminary clinical efficacy
Phase 3: extensive clinical trials

NDS review by the TPD

Phase 4: post-marketing surveillance

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29
Q

How are phase 1 trials initiated?

A
  • studies healthy volunteers with single and multi-doses starting at 1/10th of the NOAEL in the most sensitive animal species
  • concurrent pharmacokinetic monitoring and no more than 3 dose increments in 1 subject
  • monitoring adverse events and biochemical response markers
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30
Q

What is the purpose of phase 1 clinical trials?

A
  • pharmacologic profiling

- safe dose escalation to pharmacodynamic activity and/or toxicity

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31
Q

Who are the subjects involved in phase 1 clinical trials?

A

Normal volunteers, except for potentially toxic drugs; desirable to use patients

20-100 subjects typically

32
Q

What is the setting of phase 1 clinical trials?

A
  • No concomitant therapy unless mandatory
  • 2-4 weeks washout of any prior drugs
  • Starting dose 1/10th of NOAEL in most sensitive animal test
  • prolonged placebo-controlled (4-6 weeks)-
33
Q

What is a proof-of-concept test and what are they used for?

A

First use of patients used to establish efficacy within the boundaries of AEs and key parts of the MOA

Given chemistry, stability and bioavailability, is it practical to achieve the target efficacy?

What are the early signs of safety concerns in organ systems?

34
Q

What is examined during phase 2a trials?

A

Dose-response relationships, efficacy and safety variability across patient subgroups, special population pharmacokinetics and metabolic pathways

**important for toxic metabolites and figuring out dose frequency options

35
Q

What are phase 2b trials for?

A

Narrowing the target population and route of administration for a controlled trial

36
Q

What is the purpose of phase 2 trials overall?

A
  • explore early efficacy and safety in patients (dose selection/interval, use of surrogate measures)
  • early ADME data to guide phase 3 design
37
Q

What are the characteristics of the subjects involved in phase 2 clinical trials?

A
  • ordinarily only targeted at one disease or condition
  • late phase 2 patients may have disease/therapy in addition to the targeted disease
  • seldom more than 200 patient subjects
38
Q

What are the regulatory approval requirements from clinical 3 trials?

A
  • requires finalization of formulation and equivalency with various earlier versions and a draft product monograph
  • address potential safety problems from animal testing and prior phases
  • 1000-3000 patients with specific disease
39
Q

What is the additional measure that is accounted for in phase 3 clinical trials other than efficacy and safety?

A

Quality of life measures

  • physical and mental subject wellbeing
  • physical and mental objective functioning
40
Q

Who are the subjects typically involved in phase 3 clinical trials?

A
  • large controlled trials in patients with targeted disease
  • two or more multi-center trials comprised of several thousand patient-subjects
  • rigorous exclusion and inclusion criteria
  • placebo and or active drug-controlled design
41
Q

What are the considerations for phase 3 trials?

A
  • placebo controlled design is the least ambiguous
  • ethics of placebo-controlled studies
  • drug-drug interactions
  • looking for clinically meaningful outcomes
42
Q

What is the NDA or the NDS?

A 
NDA = New Drug Application
NDS = New Drug Submission (Canadian)

Submitted to the regulatory authorities for review which takes 6-12 months depending on priority.

Contains all information that is known about the drug, chemical, pre-clinical and clinical studies (200-500 volumes of material)

43
Q

What are the steps in the Drug Approval Process in Canada?

A
  1. Developer can request pre-submission meeting with TPD before NDS
  2. NDS to TPD describes the drug, quality, summary of clinical trials, AEs, and pre-clinical data
  3. First screening by TPD is done within 45 days
  4. Technical and detailed review takes 300 days
  5. Successful applications are issued a NOC and assigned a DIN
  6. Adverse reaction reporting system is updated (MedEffect Canada)
44
Q

What does NOC stand for?

A

NOC = Notice of compliance

45
Q

What are the goals of post marketing phase 4/5 clinical trials?

A
  • further elucidation of adverse events and/or pharmacology
  • large scale/long term assessment of morbidity and mortality
  • further testing of drug which were released prior to full assessment of safety in the interest of public health
  • special populations
46
Q

What are black box warnings?

A

Warnings about AEs, risk and interactions for certain medications

Adverse event reporting program - MedWatch (HCPs, consumers and manufacturers)

47
Q

What is the cost of drug discovery?

A

$0.5 million

48
Q

What is the cost of product selection?

A

$0.5 million

49
Q

What is the cost of pre-clinical studies?

A

$1-1.5 million

50
Q

What are the costs of each phase of clinical trials?

A

Phase 1 –> $5-10 million

Phase 2 –> $10-20 million

Phase 3 –> $30-50 million

51
Q

What is the cost of product launch?

A

$5-10 million

52
Q

What are fast track applications?

A

Introduced in 1997 to treat serious conditions and fill unmet medical need with the purpose to get new drugs to patients earlier.

Generally requested by the developer

53
Q

What is PRV?

A

PRV = Priority review voucher

A program to develop ‘material threat’ medicines

54
Q

What is an orphan drug?

A

A drug made for a rare disease or condition

55
Q

What is the major pitfall of clinical trials?

A

The approval process is fundamentally sound but extends over thousands of sites and people introducing room for error

56
Q

What is ACRP?

A

ACRP = Association of Clinical Research professionals

Deals with certification of investigators

57
Q

What is AAHRPP?

A

AAHRPP = Association for the Accreditation of Human Research Protection Program

USA and Canada are associated here

58
Q

What is HPFBI?

A

HPFBI = Canada’s Health Products and Foods Branch Inspectorate

59
Q

What is the difference between GLP and GMP?

A

GLP = Good Laboratory Practices

GMP = Good Manufacturing Practices

60
Q

What is ISMP?

A

ISMP = institute for safe medication practices

Canadian independent not-for-profit organization founded in 1994

61
Q

What is the Sponsors’ Table for Human Research Participant Protection in Canada?

A

2007 –> An expert committee identified areas for harmonization under the framework of a new, national oversight system for Policy, Education and Accreditation of Review Ethics Boards

62
Q

What is the most common reason that a drug fails the clinical trial phase?

A

Pharmacokinetics

2nd most common is the lack of efficacy

63
Q

What is BGTD and what do they do?

A

BGTD = biologics and Genetic Therapies Directorate

Oversees approvals for biological products including blood, blood products, viral/bacterial vaccines, cells, tissues, organs and antibodies

64
Q

What is NHPD and what do they do?

A

NHPD = Natural Health Products Directorate

Oversees approval of vitamins, minerals, herbal and homeopathic remedies, traditional Chinese medicines etc

65
Q

What are the risks associated with clinical trials?

A

1) Expensive
2) Low success rates
3) need to monitor and refine the regulatory processes constantly

66
Q

What is involved in the post-approval (phase 4) section of the drug development process?

A
  • prescription drug
  • marketing
  • advertising
  • surveillance
  • adverse reaction reporting
  • inspections
  • surveys
67
Q

What does Imatinib treat and how does it do so?

A

Used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumours (GIST), and lymphoblastic leukemia

Binds to ableson kinase (BCR-ABL) in cancer cells

68
Q

Who discovered Imatinib?

A

Discovered by CIBA-Geigy, Basel, Switzerland in the 1990’s

69
Q

Why are protein kinases molecular targets in oncology?

A

Protein kinases are involved in phosphorylation –> protein phosphorylation is implicated in cell proliferation and differentiation in cancer pathophysiology

70
Q

How are PK’s classified and what type of PK does Imatinib target?

A

PK’s are classified as serine/threonine, tyrosine, histidine, or mixed type

Idk which one is targeted by imatinib he didn’t post the TopHat questions

71
Q

What is the MOA of Imatinib?

A

Replaces ATP on the Abelson Kinase (BCR-ABL) to prevent phosphorylation of tyrosine

72
Q

What is Lipinski’s rule of 5?

A

A potential drug candidate should have the following features:

1) 5 or fewer H bond donors
2) MW <500
3) Log P <5
4) 10 or less H bond acceptors

73
Q

What is the name of the base discovered to be a promising protein kinase inhibitor?

A

Phenylamoniopyrimidine

This is the pharmacophore for Imatinib

74
Q

What is the IC50?

A

IC50 = inhibitory concentration

The concentration of a test compound required to inhibit 50% of the enzyme/protein activity

75
Q

What is found in the activation loop of kinases?

A

Aspartic acid, phenylalanine and glycine (phosphorylation loop/DFG region)

When you move it away from the active site, the allosteric site is opened where Imatinib binds

76
Q

What is the class of Imatinib?

A

Type 2 Kinase inhibitor

77
Q

What are the types of binding that are possible with Imatinib?

A

1) Hydrophobic
2) Hydrogen bonding
3) Van der waals

PHARM 141 (8 decks)

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